Parasitic helminths infect over 2 billion people worldwide. They cause significant morbidity and mortality in developing areas of the world, especially among children. An effective vaccine against any type of human helminth infections has been elusive, partly because there is a poor understanding of how to induce protective immunity against these parasites. Parasitic helminths induce a CD4+ TH2 driven immune response. This response is necessary not only to expel the parasite, but also to repair tissue damage caused by infection and mitigate any further pathology resulting from chronic persistence. The development of an effective vaccine to helminths may require a meticulous understanding of the mechanism of CD4+ memory T cell formation and function. Certain subsets of CD4+ and CD8+ T cells will express the chemokine receptor CX3CR1 during inflammation and infection. CX3CR1 expression on CD8+ T cells can help predict memory phenotypes during viral infections. The role of CX3CR1+ CD4+ T cells during type-2 immune responses induced by helminth infection is completely unknown. We have recently found that CX3CR1+ CD4+ T cells accumulate in the tissues affected by helminth infections, but not in the draining lymph nodes. During Schistosoma mansoni infection CX3CR1+ CD4+ T cells accumulate in the liver during granuloma formation. During Nippostrongylus brasiliensis infection these cells rapidly accumulate in the lungs. The goal of this proposal is to further characterize the phenotype and function of this population of CD4+ T cells, through two specific aims. In the first Aim, we will test the hypothesis that CX3CR1+ CD4+ T cells from inflamed tissues during helminth infection can differentiate into T follicular helper cells after trafficking to the spleen. In the second Aim, we will determine if CX3CR1+ CD4+ T cells contribute to germinal center formation, antibody responses and host protection against secondary infection. Overall, the study we propose will increase our understanding of CD4+CX3CR1+ cells in the tissues of helminth infected mice, during a type-2 immune response. This population of T cells is poorly understood and may be important for supporting antibody responses, parasite expulsion, protective immunity and tissue repair. Utilizing genetic fate-mapping and conditional depletion systems, we can thoroughly characterize their phenotype and function during helminth infections.